WO2023016543A1 - Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et ses diverses utilisations médicales - Google Patents

Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et ses diverses utilisations médicales Download PDF

Info

Publication number
WO2023016543A1
WO2023016543A1 PCT/CN2022/112014 CN2022112014W WO2023016543A1 WO 2023016543 A1 WO2023016543 A1 WO 2023016543A1 CN 2022112014 W CN2022112014 W CN 2022112014W WO 2023016543 A1 WO2023016543 A1 WO 2023016543A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
iiib
hydrogen
group
alkyl
Prior art date
Application number
PCT/CN2022/112014
Other languages
English (en)
Chinese (zh)
Inventor
詹正云
Original Assignee
上海爱博医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海爱博医药科技有限公司 filed Critical 上海爱博医药科技有限公司
Publication of WO2023016543A1 publication Critical patent/WO2023016543A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to a new class of urea compounds formed by "multi-substituted aromatic amines and alkyl amines". More specifically, the present invention relates to polysubstituted aryl aminourea compounds useful as multi-target tyrosine kinase inhibitors and various medical applications thereof.
  • Protein tyrosine kinases are the largest known protein superfamily, and protein tyrosine kinases are an important hub for the transmission of extracellular signals into cells. Tyrosine kinases play an important role in regulating cell proliferation and differentiation. Abnormal expression of PTK will activate a series of downstream signaling pathways, causing cascade reactions, resulting in disordered cell proliferation regulation, and eventually leading to tumor formation. Tyrosine kinases can be divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).
  • RTKs receptor tyrosine kinases
  • nRTKs non-receptor tyrosine kinases
  • Receptor tyrosine kinases include vascular endothelial growth factor receptor (VEGFR, Vascular Endothelial Growth Factor Receptor), Fibroblast Growth Factor Receptor (FGFR, Fibroblast growth Gactor Receptor), Epidermal Growth Factor Receptor [Epidermal growth factor receptor, referred to as EGFR, HER1, or ErbB-1, is epidermal growth factor receptor HER family member], tyrosine kinase membrane receptor (c-Met), platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), and RET and other members, these RTKs are related to tumor diseases and their target Treatment is closely related.
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptor
  • Epidermal Growth Factor Receptor Receptor Epidermal Growth Factor Receptor
  • EGFR vascular endothelial growth factor receptor
  • TKIs protein tyrosine kinase inhibitors
  • TKIs protein tyrosine kinase inhibitors
  • TKIs protein tyrosine kinase inhibitors
  • clinical Small molecule urea compound anticancer drugs for the treatment of liver cancer include Sorafenib (Sorafenib, Ref-1), Regorafenib (Regorafenib, Ref-2), and tyrosine kinases VEGFR1-3 and FGFR1- Lenvatinib (Lenvatinib, Ref-3), all of which have good inhibitory effects, has a good anti-tumor effect in clinical treatment.
  • the purpose of the present invention is to develop a novel multi-target tyrosine kinase inhibitor (TKI) with higher activity of inhibiting tyrosine kinase and lower toxicity and side effects through the innovative design of small molecule structure and functional groups thereof. It is effectively used to treat various tumors such as pancreatic cancer, lung cancer, kidney cancer, liver cancer, gastric cancer, cervical cancer and leukemia and related cancer diseases.
  • TKI multi-target tyrosine kinase inhibitor
  • the present invention relates to a class of multi-substituted anilaminourea compounds of the formula IIIb containing novel multi-substituted aniline groups as the focus of innovation.
  • TKI multi-target tyrosine kinase inhibitor
  • VEGFR1, VEGFR2, VEGFR3 and fibroblast growth factor receptors (FGFR1-4) vascular endothelial growth factor receptors
  • FGFR1-4 fibroblast growth factor receptors
  • Tyrosine kinases such as but not limited to EGFR, RET, PDGFR ⁇ and other tyrosine kinases, can produce relatively strong angiogenesis inhibitory effects, and are more effective in preventing and treating various abnormal proliferations accompanied by angiogenesis. It has better applications in diseases such as tumors.
  • the structure of the urea compound containing multiple substituted aniline groups disclosed in the present invention is based on the structural characteristics of the tyrosine kinase target, by introducing more substituents into aniline for structural modification innovation and optimization, thereby developing a A multi-target tyrosine kinase inhibitor (TKI) with better inhibitory effect can more effectively treat various types of tumors.
  • TKI multi-target tyrosine kinase inhibitor
  • the core problem solved by the present invention is to develop a novel urea compound containing multi-substituent aniline as an innovative feature, which is effective for pancreatic cancer (BXPC3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B2. 1-7), gastric cancer (SNU16), cervical cancer (Hela), and leukemia (K562) and other tumor cell lines and kinase targets such as VEGFR1-3, FGFR1-4, EGFR, RET have good inhibitory effects, the results It shows that the suppression effect is better, the application prospect is better, and it has better security.
  • the first aspect of the present invention provides a compound represented by formula IIIb, its cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, or pharmaceutically Acceptable salts or hydrates, and deuterated or isotopically substituted compounds:
  • E is nitrogen (N), or CH;
  • G is hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
  • G2 is halogen, -CN, C 1-20 alkylamino, C 1-20 hydroxyalkyleneamine, C 1-20 nitrile alkyleneamine, C 1-20 aminoalkyleneamine group, C 3-20 aminocycloalkyleneamine group, C 1-20 carboxyalkyleneamine group, C 3-20 carboxycycloalkyleneamine group, 3-6 membered heterocyclylamine group, or -OR 6 ;
  • R 6 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 2-20 aminoalkylene, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 amino cycloalkylene, C 1-20 amino (C 3-20 cycloalkyl) alkylene, 3-6 membered heterocycl
  • G 3 is -CN, -C(O)OR, -C(O)NH 2 , deuterated -C(O)ND 2 , C 1-20 alkoxy, C 1-20 alkylamino, or - C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-20 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 1-20 haloalkane C 1-20 cyanoalkylene, C 3-20 cyanocycloalkylene, C 2-20 hydroxyalkylene, C 3-20 hydroxycycloalkylene, C 2-20 aminoalkylene Group, C 3-20 aminocycloalkylene, C 2-20 carboxyalkylene, C 3-20 carboxycycloalkylene, C 3-20 cycloalkenyl, C 3-20 cycloalkyl, 3- 6-membered heterocyclic group, 3-6-membered heterocyclic alkylene group, C 6-20 aryl group, C 3-20 heterocycl
  • G 4 and G 5 are each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-20 alkyl, C 1-20 alkoxy, or C 1-20 alkylamino;
  • R 1 is selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, or C 3-20 deuterated cycloalkyl;
  • R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 deuterated cycloalkyl, or 3-6 membered heterocyclyl;
  • X 1 , X 2 and X 3 are each independently selected from: halogen, -CN, -NH 2 , C 1-20 alkoxy, or C 1-20 alkylamine;
  • X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2 , C 1-20 alkoxy, or C 1-20 alkylamine.
  • E is nitrogen (N), or CH;
  • G is hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
  • G2 is halogen, -CN, C 1-6 alkylamino, C 1-6 hydroxyalkyleneamine, C 1-6 nitrile alkyleneamine, C 1-6 aminoalkyleneamine C 3-6 aminocycloalkyleneamine, C 1-6 carboxyalkyleneamine, C 3-6 carboxycycloalkyleneamine, 3-6 membered heterocyclylamine, or -OR 6 ;
  • R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkyl, C 3-6 amino cycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclic group, or 3-6
  • G 3 is -CN, -C(O)OR, -C(O)NH 2 , deuterated -C(O)ND 2 , C 1-6 alkoxy, C 1-6 alkylamino, or - C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-6 alkyl, R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkane C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 3-6 hydroxycycloalkylene, C 2-6 aminoalkylene Group, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 carboxycycloalkylene, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclic group, 3-6-membered heterocyclic alkylene group, C 6-10 aryl group, C 3-10 heterocycl
  • G 4 and G 5 are each independently selected from: hydrogen, deuterium (D), halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino;
  • R 1 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, or C 3-6 deuterated cycloalkyl;
  • R 2 and R 3 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, or 3-6 membered heterocyclyl;
  • X 1 , X 2 and X 3 are each independently selected from: halogen, -CN, -NH 2 , C 1-6 alkoxy, or C 1-6 alkylamine;
  • X 4 is selected from: hydrogen, deuterium, halogen, -CN, -NH 2 , C 1-6 alkoxy, or C 1-6 alkylamine.
  • E is CH
  • G1 is hydrogen
  • G 2 is -OR 6 , wherein R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkylene, C 3-6 aminocycloalkylene, C 1-6 amino (C 3-6 cycloalkyl) alkylene, 3-6 membered heterocyclyl, or 3-6 membered heterocyclylalkylene ;
  • G 3 is -C(O)OR, -C(O)NH 2 , or -C(O)NR 4 R 5 ; wherein, R is hydrogen, or C 1-6 alkyl, and R 4 and R 5 are independently is selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene, C 2-6 aminoalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, 3-6 heterocyclyl, C 1-6 alkylene (3-6 hetero ring), C 3-6 heterocyclic aryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2-6 heterocycloalkylsulfonyl; between R 4 and R 5 Occasionally connected to each other to form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 heteroatoms;
  • G4 and G5 are each independently selected from: hydrogen;
  • R is selected from: hydrogen
  • R is selected from: hydrogen
  • R 3 are each independently selected from: C 3-6 cycloalkyl
  • X 1 , X 2 and X 3 are each independently selected from: halogen;
  • X4 is selected from: hydrogen.
  • the compound of formula IIIb described in the present invention is selected from the following structures, characterized by including but not limited to any of the following structures:
  • the second aspect of the present invention provides a method for preparing a compound represented by formula IIIb, characterized in that: it can be prepared by any of the following two methods:
  • R 4 and R 5 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 2-6 hydroxyalkylene, C 2 -6 aminoalkylene, C 2-6 carboxyalkylene, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, 3 -6-membered heterocyclylalkylene, C 6-12 aryl, C 3-10 heterocyclic aryl, C 1-6 alkylsulfonyl, C 3-6 cycloalkylsulfonyl, or C 2- 6 heterocycloalkylsulfonyl groups, or R 4 and R 5 are connected to each other to form a 3-8 membered heterocyclic group or heterocyclic aryl group containing 1-3 heteroatoms.
  • R 6 is selected from: hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkylene, C 3-6 cyanocycloalkylene, C 2-6 hydroxyalkylene Alkyl, C 2-6 aminoalkylene, C 3-6 aminocycloalkylene, C 2-6 carboxyalkylene, C 3-6 cycloalkyl, C 3-6 aminocycloalkylene group, C 1-6 amino group (C 3-6 cycloalkyl) alkylene group, 3-6 membered heterocyclyl group, or 3-6 membered heterocyclylalkylene group.
  • Another aspect of the present invention further provides a synthetic preparation method for the following intermediate compound RM1b-01:
  • Another aspect of the present invention further provides the synthetic preparation method of the following compound SM2-01 and its application in the synthetic preparation of the compound of formula IIIb:
  • Another aspect of the present invention provides a compound represented by formula IIIb or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent and/or excipient.
  • Another aspect of the present invention provides an application of a compound represented by formula IIIb or a composition thereof in the preparation of a medicament for preventing or treating blood system diseases.
  • Another aspect of the present invention provides an application of a compound represented by formula IIIb or a composition thereof in the preparation of a medicament for treating cancer, wherein the cancer is selected from: pancreatic cancer, lung cancer, kidney cancer, liver cancer, gastric cancer , cervical cancer and leukemia and other cancer diseases.
  • Another aspect of the present invention provides a combination drug product comprising a compound according to any one of formula IIIb or a compound according to claim 6, and an additional pharmaceutically active agent selected from the group consisting of: (1 ) immunomodulators; (2) PD-1; (3) PD-L1; or (4) other compounds that do not belong to the above (1)-(3).
  • the additional pharmaceutical active agent is selected from: (1) immunomodulator; (2) PD-1; (3) PD-L1; or (4) not belonging to the above (1)-( 3) other compounds.
  • the immunomodulator includes but not limited to Car-T or other immunomodulators.
  • the PD-1 contains active agents that have been marketed or are in clinical trials, including but not limited to: Opdivo, Keytruda, JS001, SHR-1210, BGB-A317, ICI308, BAT1306, toripalimab, or sintilimab.
  • the PD-L1 contains active agents that have been marketed or are in clinical trials, including but not limited to: recombinant fully human anti-PD-L1 monoclonal antibody injection, Tecentriq, Bavencio , lIctayo, Imfinzi or Acradine soft capsules.
  • the compound or composition of the present invention is especially suitable for the treatment of cancer or related inhibition of angiogenesis, prevention and treatment of blood system diseases.
  • the compound of the present invention has better multi-target selectivity and inhibitory activity.
  • the "alkyl” refers to a branched chain, straight chain, monocyclic and polycyclic saturated alkane group including 1 to 20 carbon atoms, which consists only of carbon and hydrogen atomic composition.
  • the alkyl group has one to twelve carbon atoms (C1C12 alkyl), one to eight carbon atoms (C1C8 alkyl) or one to six carbon atoms (C1C6 alkyl), and it is passed through a single Bonds connect to the rest of the molecule.
  • An alkyl group can be unsubstituted or substituted with one or more substituents.
  • the alkyl group contains 1-9 carbon atoms (eg, 1-6 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms).
  • Exemplary alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and each isomers etc.
  • the alkyl group including one or more carbons thereof, may optionally be linked to one or more groups including, but not limited to, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl group, carboxyl group, amino group (NH2), amino group, alkylamino group, aminocarbonyl group, aminocarbonyl group, alkyl group, alkoxy group, alkoxycarbonyl group, alkylcarbonylamino group, alkoxycarbonylamino group , Alkylaminocarbonyl, Cycloalkyl, Cycloalkenyl, Cycloalkoxy, Cycloalkoxycarbonyl, Cycloalkylamino, Cycloalkylaminocarbonyl, Cycloalkenyl, Cycloether, Heterocyclyl , alkyl ureido, aryl, aryloxy, heteroaryl, heteroaryloxy, fused aryl, fused heteroaryl, fused epoxy, fuse
  • cycloalkyl refers to a ring system containing only carbon atoms in the ring system backbone, eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
  • a carbocyclyl can include multiple fused rings.
  • a carbocyclyl can have any degree of saturation provided at least one ring in the ring system is not aromatic.
  • a carbocyclyl group can be unsubstituted or substituted with one or more substituents.
  • a carbocyclyl group contains 3 to 10 carbon atoms, such as 3 to 6 carbon atoms.
  • the "aryl” refers to any stable monocyclic, bicyclic, tricyclic or tetracyclic rings containing up to 7 carbon atoms in each ring, wherein at least one ring It is a hydrocarbon ring system group of an aromatic ring.
  • exemplary aryl groups are hydrocarbon ring system groups comprising hydrogen and 6-9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups comprising hydrogen and 9-12 carbon atoms and at least one aromatic ring; comprising hydrogen and a hydrocarbon ring system group of 12-15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group comprising hydrogen and 15-18 carbon atoms and at least one aromatic ring.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl groups include, but are not limited to, aryl groups derived from benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like.
  • the "heterocyclic group” has 3-16 ring atoms, including 1-3 (if it is a monocyclic ring), and 1-6 (if it is a bicyclic ring) or 1-9 (if tricyclic or polycyclic) one or more of heteroatoms selected from O, N and S are aromatic or non-aromatic heterocycles containing 0 to 3 carbon-carbon double bonds, and Included are bicyclic and tricyclic fused ring groups.
  • "Heterocyclic” moieties may contain from 3 to 14 carbon atoms, eg 3 to 8 carbon atoms in monocyclic systems and 7 to 14 carbon atoms in polycyclic systems.
  • Heterocycle encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
  • the heterocyclyl can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, iso Oxazolidines, thiazolidines, isothiazolidines, piperidines, morpholines, thiomorpholines, piperazines and tetrahydropyrans.
  • heterocyclic group includes the above-mentioned heterocyclic aryl groups and their dihydro or tetrahydro analogs, and includes but is not limited to the following “heterocyclic groups”: benzimidazolyl, benzofuranyl, benzopyrazolyl , benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuryl, pyridopyridyl, and heterocyclic groups can be combined with other organic small molecule groups through carbon atoms or heteroatoms Groups are connected into new compounds with medicinal effects.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention first designs and introduces a new type of "multi-substituted arylamine and alkylamine” functional groups, and synthesizes a class of drugs that can more effectively treat various tumors and other diseases that are accompanied by abnormal proliferation of blood vessels. Polysubstituted anilinourea compounds.
  • the present invention generally relates to compounds covered by formula IIIb, and cis-trans isomers, enantiomers, diastereoisomers, racemates, tautomers, or pharmaceutically acceptable Salts or hydrates, and deuterated or other isotopically substituted compounds:
  • the compound of formula IIIb, E, G 1 , G 2 , G 3 , G 4 , G 5 , R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 etc. are as defined in the claims and described in the manual. Specific embodiments of the compound of formula IIIb are also described below.
  • the compounds of the present invention can exist in multiple isomeric forms, and one or more tautomeric forms, including two single tautomers, and a mixture of tautomers.
  • the term "isomer" is intended to cover all isomeric forms of the compounds of the invention, including tautomeric forms of said compounds.
  • pharmaceutically acceptable salt is a pharmaceutically acceptable, organic or inorganic acid or base salt of the compound of the present invention.
  • typical pharmaceutically acceptable salts are selected from but not limited to any of the following acids or bases: inorganic acid salts are mainly selected from: hydrochloride, bromate, iodate, phosphate, sulfate, bicarbonate Salt, bisulfate, borate, or nitrate; organic acid salt is mainly selected from: acetate, benzoate, methanesulfonate, tosylate or valerate.
  • Compounds of the invention may be isotopically labeled in which one or more atoms are replaced by atoms having a different atomic mass or mass number.
  • isotopes that can be incorporated into compounds of formula IIIb include: isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, or chlorine. Examples of such isotopes are respectively: 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 36 Cl.
  • These radiolabeled compounds can be used to measure the biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissues, including subjects administered the labeled compounds.
  • Labeled compounds are also used to determine therapeutic efficacy, site or mode of action, and binding affinity of candidate therapeutics to pharmacologically important targets. Certain radioactively labeled compounds of formula IIIb are therefore useful in drug and/or tissue distribution studies.
  • the radioisotopes tritium, ie3H , and carbon-14, ie14C are particularly useful for this purpose because of their ease of incorporation and ready means of detection.
  • D deuterium
  • 2H can confer certain therapeutic advantages resulting from greater metabolic stability (eg, increased in vivo half-lives of deuterium-containing compounds).
  • Substituting deuterium for hydrogen can reduce the dosage required to achieve a therapeutic effect and thus may be preferred for use in a discovery or clinical setting.
  • Isotopically-labeled compounds of formula IIIb can generally be prepared by conventional techniques known to those skilled in the art or in a manner analogous to those described in the Preparations and Examples sections described hereinafter, using suitable isotopically-labeled reagents.
  • Embodiments of the invention described herein are also intended to encompass in vivo metabolites of compounds of formula IIIb. These products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. processes which are primarily attributable to the enzymatic activity of the compounds of the invention upon administration.
  • the present invention also provides pharmaceutically acceptable salt forms of the compound of formula IIIb.
  • the scope of this invention encompasses acid addition salts which are formed by contacting a pharmaceutically suitable acid with a compound of this invention.
  • “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed using inorganic acids such as, but not limited to , hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, etc.;
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist in hydrated forms, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms.
  • the compounds of the invention may be true solvates, while in other cases the compounds of the invention may retain only adventitious water or a mixture of water plus some adventitious solvent.
  • the compound of formula IIIb is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of formula IIIb which is effective after administration of the pharmaceutical composition to a mammal. for the treatment of a particular disease or condition of interest.
  • the pharmaceutical compositions of the present invention may comprise a compound of formula IIIb in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof may also be administered prior to, concurrently with, or subsequent to the administration of one or more other therapeutic agents.
  • Such combination therapy includes the administration of a single pharmaceutical dosage formulation comprising the compound of the invention and one or more other active substances, as well as the administration of the compound of the invention and each active substance in separate pharmaceutical dosage formulations.
  • the present invention optimizes and synthesizes some novel tyrosine kinase (RTK) inhibitor formula IIIb urea compounds from the structure of urea anticancer drugs, and has several important RTK targets (such as: VEGFR1, VEGFR2 ( KDR), VEGFR3, FGFR2, RET, etc.) have better inhibitory effects.
  • RTK tyrosine kinase
  • Some novel formula IIIb urea compounds of the present invention are effective against various tumor cell lines [such as: pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), and leukemia (K562), etc.] have better inhibitory effects, can be used as targeted drugs to effectively treat some tumors or related cancers mediated by RTK kinases, and have better RTK target to selectivity and security.
  • tumor cell lines such as: pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), and leukemia (K562), etc.
  • All raw materials for example: SM1, SM2, SM3, SM4
  • reagents and solvents used in the present invention can be obtained commercially or by order.
  • the synthetic reaction routes, methods and conditions involved in the preparation of various new compounds of general formula IIIb are the conventional well-known reaction routes, methods and conditions in the art. According to the following synthetic preparation methods disclosed in the present invention, those in the art A skilled person can use the same principle and method to prepare each specific compound involved in each general formula compound in the present invention.
  • the synthetic reaction routes, methods and conditions involved in the preparation of various new compounds of formula IIIb are conventional routes, methods and conditions in the art. According to the following synthetic preparation methods disclosed in the present invention, those skilled in the art can use According to the same principle and method, different reagents such as SM1 (Table 1), SM2 (Table 2), SM3 (Table 4a), SM4 (Table 4b) can be selected respectively by the conventional synthetic method shown in the following synthetic reaction scheme 1
  • SM1 Table 1
  • SM2 Table 2
  • SM3 Table 4a
  • SM4 Table 4b
  • the present invention optimizes the following three methods for synthesizing the compounds of formula IIIb series through the study of synthesis-related reaction conditions.
  • R 4 , R 5 and R 6 are the same as those of R 4 , R 5 and R 6 in claims 1 to 5 respectively;
  • intermediate RM2 (1.0eq) and reagent SM3 (1.0 ⁇ 5.0eq), pyridine (1.0 ⁇ 5.0eq) in a round bottom reaction flask dissolved in DMF (5 ⁇ 10x), react at 20 ⁇ 80°C, wait until HPLC After the completion of the reaction, the intermediate RM3 was obtained after routine operations such as post-treatment, column chromatography purification, and drying.
  • R 4 , R 5 and R 6 are the same as those of R 4 , R 5 and R 6 in claims 1 to 5;
  • Table 3a Structural formulas of the "RM1" series of substitution etherification reaction products in the first step of synthesis method
  • Table 5a Structural formulas of deuterated isotope compounds of formula IIIb polysubstituted aryl ureas
  • the mass spectrometry data was analyzed by using liquid phase 1260 and mass spectrometer 6120 produced by Agilent.
  • the molecular weight of the compound of formula IIIb in the present invention is mainly based on positive ion mode ESI-MS [(M+H) + ].
  • the special raw materials and intermediates involved in the present invention are provided by Shanghai Zannan Technology Co., Ltd., etc., and all other chemical reagents are purchased from reagent suppliers such as Shanghai Reagent Company, Aldrich Company, and Acros Company. If the intermediates or products required for the reaction in the synthesis process are not enough for the next step and other tests, the synthesis is repeated many times until a sufficient amount is obtained.
  • the activity test, pharmacology, toxicology and other tests of the compounds prepared in the present invention are completed by CRO service companies in Shanghai, Beijing and other places according to industry regulations.
  • CDI N,N'-carbonyldiimidazole
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HMTA Hexamethylenetetramine
  • PE petroleum ether
  • Preparation of the diazonium salt of p-aminobenzenesulfonic acid Add p-aminobenzenesulfonic acid (60g, 1.00eq), water (500mL) and Na2CO3 (20.0g) into a 1L three-necked flask, stir until clear, and control the internal temperature to 0°C , drop NaNO2 (25.0g) in water (75mL) solution, after dropping, add concentrated hydrochloric acid (86mL) dropwise, control internal temperature ⁇ 5°C, then stir for 40 minutes (refrigerate for later use).
  • Fluorine nuclear magnetic resonance spectrum data of product SM2-01 hydrochloride 19F-NMR (377MHz, d4CD3OD) ⁇ : -132.36/-132.40/-133.09/-133.13.
  • intermediate RM1-23 (3.95g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
  • HPLC HPLC shows that the reaction is over
  • the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-23 (3.45g ), yield: 67%;
  • Step 1 In a 50mL single-necked bottle, add raw material SM1-01 (2.52g, 10mmol), SM2-01 (2.12g, 13mmol), potassium tert-butoxide (1.46g, 13mmol) and DMSO (20mL), nitrogen Protection, reaction at 85°C, after HPLC showed that the reaction was over, the reaction solution was cooled to room temperature, slowly poured into 100mL ice water, solids were precipitated, filtered, washed with water, and fully dried to obtain intermediate RM1-24 (2.95 g), yield: 78%;
  • the second step in the three-neck flask of 100mL, add intermediate RM1-24 (3.78g, 10mmol), DMF (20mL) and pyridine (30mmol), ice-water bath control does not exceed 10 °C, drop into chloroformate phenyl ester (30mmol ), react at room temperature after dripping, after the HPLC shows that the reaction is over, the reaction solution is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain the intermediate RM2- 24 (3.64g), yield: 73%;
  • Step 3 Add intermediate RM2-24 (4.98g, 10mmol), MeCN (50mL) and SM3-01 (30mmol) to a 100mL single-necked bottle, and react at 60°C. After the reaction, HPLC shows that there is solid precipitation , filtered, washed and dried, purified by column chromatography to obtain solid product RM3-02 (2.63g), yield: 57%.
  • Step 4 Add intermediate RM3-02 (4.61g, 10mmol), THF (10mL), MeOH (10mL) and sodium hydroxide (30mmol) to a 100mL single-necked bottle, react at 40°C, HPLC shows that the reaction is complete Finally, after adjusting the pH to about 6 with dilute acid, a solid precipitated out, filtered, washed and dried to obtain the solid product RM4-02 (3.53g), yield: 79%.
  • Step 5 Add intermediate RM4-02 (447mg, 1.0mmol), DMF (5mL), HATU (1.3mmol) and SM4-01 (1.5mmol) to a 100mL single-necked bottle, and drop into DIEA (3.0mmol) , reacted at 20°C, HPLC showed that after the reaction was completed, solids were precipitated after adding water, filtered, washed and dried, and purified by column chromatography to obtain solid product IIIb-02 (308mg), yield: 67%.
  • the synthetic method for preparing compound IIIb-05 is the same as in Example 2, wherein in the fifth step reaction, compound SM4-11 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, which is dried after the same post-treatment, Purified by column chromatography to obtain solid product IIIb-05 (401 mg), yield: 77%.
  • intermediate RM1-25 (3.62g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
  • HPLC HPLC shows that the reaction is over
  • the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-25 (4.10g ), yield: 85%;
  • intermediate RM1-26 (3.74g, 10mmol), DMF (20mL) and pyridine (30mmol), control the ice-water bath not to exceed 10°C, drop in phenyl chloroformate (30mmol), and drop
  • HPLC HPLC shows that the reaction is over
  • the reaction liquid is cooled, slowly poured into 100mL water, solids are precipitated, filtered, washed with water, dried, and purified by column chromatography to obtain intermediate RM2-26 (3.95g ), yield: 80%;
  • the synthetic method for preparing compound IIIb-31 is the same as that of Example 2, wherein in the fifth step reaction, compound SM4-25 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, which is subjected to the same aftertreatment and Purified by column chromatography to obtain a solid.
  • the synthetic method for preparing compound IIIb-36 is the same as that of Example 2, wherein in the fifth step reaction, the compound SM4-30 (1.5 mmol) is used to react with the intermediate RM4-01 to form an amide bond product, which is dried after the same post-treatment. Purified by column chromatography to obtain solid product IIIb-36 (387 mg), yield: 69%.
  • the synthetic method for preparing compound IIIb-51 is the same as the first four steps of Example 1, wherein in the fifth step reaction, compound SM4-45 (1.5 mmol) is used to react with intermediate RM4-01 to form an amide bond product, and after the same After work-up, purification by column chromatography yielded a solid.
  • the synthetic method for preparing compound IIIb-61 is the same as in Example 55, wherein in the third step reaction, compound SM1-08 (1.0mmol) is used to react with intermediate RM1b-01 (1.3mmol), and column chromatography after the same post-treatment Purification afforded a solid product.
  • SM1-14 (10.0g, 35mmol), RM1b-01 (11.8g, 45mmol), potassium tert-butoxide (5.0g, 45mmol) and dimethyl sulfoxide (100mL) in a 1.0L three-necked flask, heated to 65°C for reaction , after the reaction, cold cut and drop into ice water (1L), stirred, filtered, washed with appropriate amount of water, dried to obtain IIIb-50 (12.8g), yield: 71%.
  • Embodiment 69 In vitro inhibitory activity drug effect test
  • the compounds prepared by the present invention can be preliminarily determined and screened for their effects on pancreatic cancer (BXPC3), lung cancer (A549), renal cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer (SNU16), cervical cancer (Hela), and leukemia (K562) and other seven tumor cell line target inhibition effects, and further through the inhibition of VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET and other RTK targets.
  • the determination of the activity screens better new anti-cancer drugs, and then finally confirms the efficacy of the new drugs through clinical trials. Other methods will also be apparent to those of ordinary skill in the art.
  • each compound to be tested and a positive reference drug were prepared with 10 concentration points, diluted in the culture medium at a concentration gradient of 1:3, and duplicated. Add 5ul of the test compound or positive reference drug to the cell plate, the final concentration of the test compound is up to 10uM, the final concentration of the positive reference drug is up to 3uM, and the DMSO concentration is controlled below 0.2%, and then the cell plate is placed in the cell culture incubator Incubate for 72 hours.
  • Buffer configuration 50mM HEPES, pH 7.5, 0.00015% Brij-35.
  • the kinase is diluted to the optimal concentration with the following buffer: 50mM HEPES, pH 7.5, 0.00015% Brij-35, 2mM DTT (final concentration of enzyme reaction: VEGFR-1 (FLT1): 2nM; VEGFR-2 (KDR): 1.2 FGFR-3 (FLT4): 1.5 nM; FGFR1: 2 nM; FGFR2: 9 nM; FGFR3: 8 nM; FGFR4: 10 nM; PDGFR ⁇ : 3.5 nM; c-MET: 10 nM; RET: 7 nM; EGFR: 6 nM). Transfer 10 ⁇ l to a 384-well plate and incubate with compound for 10 minutes.
  • buffer 50mM HEPES, pH 7.5, 0.00015% Brij-35, 2mM DTT (final concentration of enzyme reaction: VEGFR-1 (FLT1): 2nM; VEGFR-2 (KDR): 1.2 FGFR-3 (
  • VEGFR1 (FLT1) 3 ⁇ M Peptide30 (5-FAM-KKKKEEIYFFFCONH 2 ), 278 ⁇ M ATP, 10 mM MgCl 2 ;
  • VEGFR2 (KDR): 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 92 ⁇ M ATP, 10 mM MgCl 2 ;
  • VEGFR3 (FLT4): 3 ⁇ M Peptide30 (5-FAM-KKKKEEIYFFFCONH 2 ), 84 ⁇ M ATP, 10 mM MgCl 2 ;
  • FGFR2 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 1.9 ⁇ M ATP, 10 mM MgCl 2 ;
  • RET 3 ⁇ M Peptide22 (5-FAM-EEPLYWSFPAKKKCONH 2 ), 23 ⁇ M ATP, 10 mM MgCl 2
  • hERG potassium ion channel
  • K + potassium ion channel
  • IKr three-phase rapid repolarization current
  • LQTS long QT syndromes
  • the compound may have the above-mentioned hidden dangers and risk. Therefore, the in vitro inhibitory effect (IC 50 ) of drugs on hERG channels has been recommended by the International Conference on Harmonization of Drug Registration as part of the preclinical safety evaluation (ICHS7B Expert Working Group, '02).
  • the stably transfected cells were dropped on a round glass slide and placed in a petri dish at a cell density below 50%, and cultured overnight.
  • the cells used in the experiment were transferred to a bath of about 1 ml embedded in the inverted microscope platform, and the extracellular fluid was perfused at a rate of 2.7 ml/min.
  • the experiment can be started after 5 minutes of stabilization.
  • Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were done at room temperature (22-24°C).
  • the electrode (BF150-110-10) was straightened using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) in the experiment.
  • the inner diameter of the electrode is 1-1.5mm, and the water resistance after being filled with inner liquid is 2-4M ⁇ .
  • the electrophysiological stimulation scheme of the hERG potassium channel is to first clamp the membrane voltage at -80mV, give the cells a continuous 2s, +20mV voltage stimulation, activate the hERG potassium channel, and then repolarize to -50mV for 5s to generate an outward tail current.
  • the stimulation frequency was once every 15s.
  • the current value is the peak value of the tail current.
  • the channel current was recorded in the whole-cell recording mode.
  • perfuse the extracellular fluid about 2 ml per minute
  • keep recording and wait for the current to stabilize (the current decay (Run-Down) is less than 5% within 5 minutes)
  • the peak value of the tail current is the control current value.
  • perfuse the extracellular fluid containing the drug to be tested and keep recording until the inhibitory effect of the drug on the hERG current reaches a steady state.
  • the peak value of the tail current is the current value after adding the drug.
  • the standard of steady state is judged by whether the latest three consecutive current recording lines coincide.
  • Some preferred compounds such as formula IIIb (such as: IIIb-06, IIIb-08, IIIb-09, IIIb-21, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65) inhibit various tumor cell lines [such as: pancreatic cancer (BXPC3), lung cancer (A549), kidney cancer (Caki-1), liver cancer (Hep3B 2.1-7), gastric cancer ( SNU16), cervical cancer (Hela), prostate cancer (PC-3), and leukemia (K562), etc.] and tyrosine kinase (such as: VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR2, RET) activity test results respectively Listed in Table 6, Table 7 and Table 8 below.
  • the activity range (IC 50 ) of each compound in inhibiting pancreatic cancer cell line (BXPC3) is ⁇ 5.0uM marked as "A", the activity range of 5.0-10.0uM is marked as “B”, and the activity range > 10.0uM is marked as "C";
  • the activity range (IC 50 ) of each compound against lung cancer cell line (A549) is marked as “A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and "C” when the activity range is >5.0uM ";
  • the activity range (IC 50 ) of each compound in inhibiting kidney cancer cell line (Caki-1) is marked as "A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and marked as “B” when the activity range is >5.0uM for "C”;
  • the activity range (IC 50 ) of each compound in inhibiting liver cancer cell lines is marked as "A” when it is ⁇ 2.5uM, "B” when the activity range is 2.5-5.0uM, and marked as “B” when the activity range is >5.0uM for "C”;
  • the activity range (IC 50 ) of each compound in inhibiting gastric cancer cell line (SNU16) is ⁇ 5.0uM marked as "A", the activity range of 5.0-10.0uM is marked as “B”, and the activity range > 10.0uM is marked as "C”";
  • the activity range (IC 50 ) of each compound against cervical cancer cell line (Hela) is marked as "A” when it is ⁇ 5.0uM, "B” when the activity range is 5.0-10uM, and "C” when the activity range is >10uM ;
  • the activity range (IC 50 ) of each compound in inhibiting the leukemia cell line (K562) is marked as "A” when it is ⁇ 5.0uM, "B” when the activity range is 5.0-10uM, and "C” when the activity range is >10uM;
  • the activity range (IC 50 ) of each compound in inhibiting prostate cancer cell line (PC-3) is marked as "A” at ⁇ 5.0uM, "B” is marked at the activity range of 5.0-10uM, and "B” is marked at the activity range>10uM C".
  • Table 7 Some preferred compounds of formula IIIb inhibit the activity results of four cell lines of liver cancer, gastric cancer, cervical cancer and leukemia
  • Some preferred compounds in formula IIIb are respectively used to inhibit the activity results of RTK targets such as VEGFR1-3, FGFR2, RET, etc. in Table 8 below; wherein, each compound inhibits various tyrosine kinases VEGFR1,
  • the active effect range (IC 50 ) of KDR (VEGFR2) and VEGFR3 is marked as "A” when it is ⁇ 5nM, "B” when the activity range is 5-10nM, and “C” when the activity range is >10nM; each compound inhibits each The active effect range (IC 50 ) of a tyrosine kinase FGFR2 is marked as "A” at ⁇ 50nM, "B” when the activity range is 50-100nM, and “C” when the activity range is >100nM; each compound inhibits each The activity effect range (IC 50 ) of a tyrosine kinase RET ⁇ 5nM is marked as "A”, the activity range of 5-10nM is marked as "B", and
  • IIIb-61 A A A A A A IIIb-65 A A A A A A Sorafenib C C C C Regorafenib C C C B C Lenvatinib B B A B B
  • Embodiment 70 Compound Toxicity Screening Test
  • the present invention respectively carried out the MTD toxicity test (150mg/kg, QD) of rats, taking the medicine for 14 consecutive days without death and other abnormalities. No abnormal changes were found in the heart, liver, lung, kidney, stomach, intestine and other organs in the rat autopsy results. It is generally believed that the tested compound is safe and non-toxic within an appropriate dose.
  • the present invention designs and synthesizes the preferred compound "IIIb-08, IIIb-09, IIIb-45, IIIb-50, IIIb-55, IIIb-56, IIIb-57, IIIb-58, IIIb-60, IIIb-61, IIIb-65" not only has better inhibitory effect, but also has better safety and druggability, and has application value for further preclinical research and clinical trials such as drug toxicology.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par la formule IIIb, un isomère cis/trans, un racémate, et un sel deutéré ou pharmaceutiquement acceptable de celui-ci, ou un mélange de l'isomère cis/trans, du racémate, et d'un sel deutéré ou pharmaceutiquement acceptable, une composition pharmaceutique contenant le composé, et une utilisation du composé en tant qu'inhibiteur cible important pour de multiples tyrosine kinases (RTK) dans le traitement de diverses maladies telles que des tumeurs accompagnées d'une angiogenèse. Le composé selon la présente invention peut être utilisé en tant que médicament à base d'anticorps polyclonal ciblant RTK ayant une meilleure activité inhibitrice pour le traitement efficace de plusieurs maladies cancéreuses telles que le cancer du pancréas, le cancer du poumon, le cancer du rein, le cancer du foie, le cancer gastrique, le cancer du col de l'utérus, et la leucémie, E, G1, G2, G3, G4, G5, R1, R2, R3, X1, X2, X3 et X4 ainsi que les marqueurs d'éléments possibles à substitution isotopique dans le composé étant tels que définis dans la description.
PCT/CN2022/112014 2021-08-12 2022-08-12 Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et ses diverses utilisations médicales WO2023016543A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110924393.5A CN113480479B (zh) 2021-08-12 2021-08-12 脲类多靶点酪氨酸激酶抑制剂及其医药应用
CN202110924393.5 2021-08-12

Publications (1)

Publication Number Publication Date
WO2023016543A1 true WO2023016543A1 (fr) 2023-02-16

Family

ID=77945137

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2022/112011 WO2023016540A1 (fr) 2021-08-12 2022-08-12 Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et son utilisation médicale
PCT/CN2022/112014 WO2023016543A1 (fr) 2021-08-12 2022-08-12 Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et ses diverses utilisations médicales

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/112011 WO2023016540A1 (fr) 2021-08-12 2022-08-12 Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et son utilisation médicale

Country Status (3)

Country Link
US (3) US12071408B2 (fr)
CN (1) CN113480479B (fr)
WO (2) WO2023016540A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113480479B (zh) * 2021-08-12 2022-08-02 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其医药应用
CN115215799B (zh) * 2022-08-12 2024-05-31 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190375714A1 (en) * 2017-02-07 2019-12-12 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Quinoline compound, preparation method and medical use therefor
CN113480479A (zh) * 2021-08-12 2021-10-08 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其医药应用

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1604665B1 (fr) * 2003-03-10 2011-05-11 Eisai R&D Management Co., Ltd. Inhibiteur de kinase c-kit
EP2956138B1 (fr) * 2013-02-15 2022-06-22 Kala Pharmaceuticals, Inc. Composés thérapeutiques et utilisations de ceux-ci
CN107698562A (zh) * 2016-08-09 2018-02-16 殷建明 一种喹啉衍生物及其用途
CN107115344B (zh) * 2017-03-23 2019-06-14 广东众生睿创生物科技有限公司 酪氨酸激酶抑制剂在制备用于预防和/或治疗纤维化疾病的药物中的用途
ES2932805T3 (es) * 2017-09-28 2023-01-26 Chongqing Pharmaceutical Industrial Res Institute Co Ltd Derivado de quinolina y aplicación del mismo como inhibidor de la tirosina quinasa
CN110845408A (zh) * 2018-08-20 2020-02-28 润佳（苏州）医药科技有限公司 同位素富集的乐伐替尼
CN117945999A (zh) * 2020-01-19 2024-04-30 重庆医药工业研究院有限责任公司 一种氟伐替尼或甲磺酸盐的晶型及其制备方法
CN111559977B (zh) * 2020-06-04 2021-06-22 广州市朝利良生物科技有限公司 一类小分子化合物及其在制备抗肿瘤转移药物中应用
CN111793027B (zh) * 2020-08-07 2021-12-03 天津理工大学 一种乐伐替尼与苯甲酸的共晶及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190375714A1 (en) * 2017-02-07 2019-12-12 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Quinoline compound, preparation method and medical use therefor
CN113480479A (zh) * 2021-08-12 2021-10-08 上海爱博医药科技有限公司 脲类多靶点酪氨酸激酶抑制剂及其医药应用

Also Published As

Publication number Publication date
US20230123696A1 (en) 2023-04-20
US20240166606A1 (en) 2024-05-23
US20230124784A1 (en) 2023-04-20
CN113480479A (zh) 2021-10-08
WO2023016540A1 (fr) 2023-02-16
CN113480479B (zh) 2022-08-02
US11912663B2 (en) 2024-02-27
US12071408B2 (en) 2024-08-27

Similar Documents

Publication Publication Date Title
CN110582483B (zh) 含邻氨基杂芳环炔基的化合物及其制备方法和用途
TW502019B (en) Aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles, and the use thereof
KR101663436B1 (ko) N-치환된 벤즈아미드 및 이의 사용 방법
WO2023016543A1 (fr) Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et ses diverses utilisations médicales
JP2020508311A (ja) アリール炭化水素受容体（ＡｈＲ）モジュレーター化合物
TW200524928A (en) Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases
CN102015707A (zh) Raf抑制剂化合物及其使用方法
CN114555586A (zh) 新颖的krasg12c蛋白抑制剂及其制备方法和用途
AU2012350482A1 (en) Imidazolidinedione compounds and their uses
WO2023098439A1 (fr) Dérivé de pyrazole, son procédé de préparation et son utilisation en médecine
CN114555588B (zh) 作为axl抑制剂的喹唑啉类化合物
TW200916458A (en) Heterocyclic compounds and methods of use thereof
EP3388428A1 (fr) Inhibiteur de la voie wnt amides hétérocycliques à cinq chaînons
WO2023016484A1 (fr) Dérivé de sulfonamide, son procédé de préparation et son utilisation médicale
CA2958741C (fr) Derive de quinazoline
WO2021063362A1 (fr) Composé de biaryle substitué par sulfo ou sel correspondant, son procédé de préparation et son utilisation
TW201823236A (zh) 聯芳組成物和調控激酶級聯之方法
WO2022194265A1 (fr) Composé à base de quinazoline, composition et utilisation d'un composé à base de quinazoline
CN112105356A (zh) 作为转运蛋白的调节剂的双环烯酮羧酸酯类化合物及其应用
CN115215799B (zh) 脲类多靶点酪氨酸激酶抑制剂及其多种医药应用
WO2022161166A1 (fr) Composé chimère de ciblage, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
JP2019520359A (ja) ビアリール尿素誘導体またはそれらの塩、およびそれらの調製方法および使用
CN110256405A (zh) 5-烃基-n-取代芳基吡啶酮衍生物及其制备方法和用途
WO2017097215A1 (fr) Inhibiteur de la voie wnt doté d'une structure urées
TWI820414B (zh) 喹唑啉類化合物、製備方法及其應用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22855523

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22855523

Country of ref document: EP

Kind code of ref document: A1